An Adamantyl Amino Acid Containing Gramicidin S Analogue with Broad Spectrum Antibacterial Activity and Reduced Hemolytic Activity

• Published in: Chemistry : a European journal 2010-10, Vol.16 (40), p.12174-12181
• Main Authors: Kapoerchan, Varsha V., Knijnenburg, Annemiek D., Niamat, Miquel, Spalburg, Emile, de Neeling, Albert J., Nibbering, Peter H., Mars-Groenendijk, Roos H., Noort, Daan, Otero, José M., Llamas-Saiz, Antonio L., van Raaij, Mark J., van der Marel, Gijs A., Overkleeft, Herman S., Overhand, Mark
• Format: Article
• Language: English
• Subjects: Adamantane - chemistry; Adamantane - pharmacology; Amino Acid Sequence; Amino Acids; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibacterial agents; Antibiotics; cationic antimicrobial peptides; Drug resistance; Erythrocytes; Erythrocytes - drug effects; Gram-Negative Bacteria - drug effects; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; gramicidin; Gramicidin - chemistry; Gramicidin - pharmacology; Hemolysis; Hemolysis - drug effects; Humans; Hydrophobicity; methicillin-resistant Staphylococcus aureus (MRSA); Models, Molecular; peptides; Peptides - chemistry; Peptides - pharmacology; Permeability; Structure-Activity Relationship; Toxicity
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201001686

The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram‐negative and Gram‐positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic. Fighting the resistance: Nine analogues of the cyclic antimicrobial peptide gramicidin S (GS) were synthesized, each with a different amphiphilic profile. These peptides were evaluated for their antibacterial and hemolytic activity. Peptide 1 (▪) displayed improved antibacterial activity and reduced hemolytic activity relative to that of the natural product (▴).